Aryl substituted pyrazoles, triazoles, and tetrazoles, and the use thereof

ABSTRACT

This invention relates to compounds having the Formula I: 
                 
 
or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein Het and R 5 -R 8  are set in the specification. The invention also is directed to the use of compounds of Formula I for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), and for the treatment, prevention or amelioration of both acute or chronic pain, as antitinnitus agents, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy.

This application claims the priority benefit under 35 U.S.C. §119 ofU.S. Provisional Application No. 60/191,757, filed Mar. 24, 2000, theentirety of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to aryl substituted pyrazoles, triazoles andtetrazoles, and the discovery that these compounds are anticonvulsantsand act as blockers of sodium (Na⁺) channels.

2. Related Art

Several classes of therapeutically useful drugs, including localanesthetics such as lidocaine and bupivacaine, antiarrhythmics such aspropafenone and amioclarone, and anticonvulsants such as lamotrigine,phenytoin and carbamazepine, have been shown to share a common mechanismof action by blocking or modulating Na⁺ channel activity (Catterall, W.A., Trends Pharmacol. Sci. 8:57-65 (1987)). Each of these agents isbelieved to act by interfering with the rapid influx of Na⁺ ions.

Recently, other Na⁺ channel blockers such as BW619C89 and lifarizinehave been shown to be neuroprotective in animal models of global andfocal ischemia and are presently in clinical trials (Graham et al., JPharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British JPharmacol. 115:1425-1432 (1995)).

The neuroprotective activity of Na⁺ channel blockers is due to theireffectiveness in decreasing extracellular glutamate concentration duringischemia by inhibiting the release of this excitotoxic amino acidneurotransmitter. Studies have shown that unlike glutamate receptorantagonists, Na⁺ channel blockers prevent hypoxic damage to mammalianwhite matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, theymay offer advantages for treating certain types of strokes or neuronaltrauma where damage to white matter tracts is prominent.

Another example of clinical use of a Na⁺ channel blocker is riluzole.This drug has been shown to prolong survival in a subset of patientswith ALS (Bensim et al., New Engl. J. Med. 330:585-591 (1994)) and hassubsequently been approved by the FDA for the treatment of ALS. Inaddition to the above-mentioned clinical uses, carbamazepine, lidocaineand phenytoin are occasionally used to treat neuropathic pain, such asfrom trigeminal neurologia, diabetic neuropathy and other forms of nervedamage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)),and carbamazepine and lamotrigine have been used for the treatment ofmanic depression (Denicott et al., J. Clin. Psychiatry 55: 70-76(1994)). Furthermore, based on a number of similiarities between chronicpain and tinnitus (Moller, A. R. Am. J. Otol. 18: 577-585 (1997);Tonndorf, J. Hear. Res. 28: 271-275 (1987)) it has been proposed thattinnitus should be viewed as a form of chronic pain sensation (Simpson,J. J. and Davies, E. W. Tip. 20: 12-18 (1999)). Indeed, lignocaine andcarbamazepine have been shown to be efficacious in treating tinnitus(Majumdar, B. et al. Clin. Otolaryngol. 8: 175-180 (1983); Donaldson, I.Laryngol. Otol. 95: 947-951 (1981)).

It has been established that there are at least five to six sites on thevoltage-sensitive Na⁺ channels which bind neurotoxins specifically(Catterall, W. A., Science 242:50-61 (1988)). Studies have furtherrevealed that therapeutic antiarrhythmics, anticonvulsants and localanesthetics whose actions are mediated by Na⁺ channels, exert theiraction by interacting with the intracellular side of the Na⁺ channel andallosterically inhibiting interaction with neurotoxin receptor site 2(Catterall, W. A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)).

Cocco, M. T.; Maccioni, A.; Plumitallo, A.; Farmaco Ed.Sci., 40: 1985;272-284 describe the two following compounds:

Other aryl substituted heterocycles are described in Stefancich, G. etal. Arch.Pharm.(Weinheim Ger.) 323: 273-280 (1990) as antimycoticagents. These compounds are described in Appendix A.

Compounds of Formula I have not been used heretofor for treating adisorder responsive to the blockade of sodium channels in a mammal.

SUMMARY OF THE INVENTION

The present invention is related to the discovery that aryl substitutedpyrazoles, triazoles and tetrazoles represented by Formula I act asblockers of sodium (Na⁺) channels.

The invention is also related with treating a disorder responsive to theblockade of sodium channels in a mammal suffering from excess activityof said channels by administering an effective amount of a compound ofFormula I as described herein.

A further aspect of the present invention is to provide a method fortreating, preventing or ameliorating neuronal loss following global andfocal ischemia; treating, preventing or ameliorating pain includingacute and chronic pain, and neuropathic pain; treating, preventing orameliorating convulsion and neurodegenerative conditions; treating,preventing or ameliorating manic depression; using as local anesthesics,antiarrhythmics, and treating tinnitus by administering a compound ofFormula I to a mammal in need of such treatment.

Another aspect of the present invention is directed to the use of thecompounds of Formula I as blockers of sodium channels.

The present invention is also directed to the use of a compound ofFormula I for the treatment of neuronal damage following global andfocal ischemia, and for the treatment or prevention of neurodegenerativeconditions, such as amyotrophic lateral sclerosis (ALS), for thetreatment of tinnitus, as antimanic depressants, as local anesthetics,as antiarrhythmics, as anticonvulsants and for the treatment orprevention of diabetic neuropathy and for the treatment of painincluding both acute and chronic pain and migraine headache.

A further aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the blockade ofsodium ion channels, containing an effective amount of a compound ofFormula I in a mixture with one or more pharmaceutically acceptablecarriers or diluents.

A number of compounds useful in the present invention have not beenheretofor reported. Thus, the present invention is also directed tonovel aryl substituted pyrazoles, triazoles and tetrazoles of Formula I.

Further, the present invention is directed to ³H and ¹⁴C radiolabeledcompounds of Formula I and their use as radioligands for their bindingsite on the sodium channel.

Additional embodiments and advantages of the invention will be set forthin the description which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, 1C, and 1C are voltage pulse protocols used to assess thepotency and kinetics of inhibition of the Na⁺ channels by the compoundsas follows: FIG. 1A: IV-curves, FIG. 1C: steady-state inactivation, FIG.1B: repriming kinetics, and FIG. 1D: time course of binding.

DETAILED DESCRIPTION OF THE INVENTION

The present invention arises out of the discovery that the arylsubstituted pyrazoles, triazoles and tetrazoles of Formula I act asblockers of Na⁺ channels. In view of this discovery, compounds ofFormula I are useful for treating disorders responsive to the blockadeof sodium ion channels.

The compounds useful in this aspect of the present invention are thearyl substituted pyrazoles, triazoles and tetrazoles represented byFormula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein

-   -   X is one of O, S, NR₉, CH₂, NR₉C(O), or C(O)NR₉ where R₉ is        hydrogen or C₁-C₁₀ alkyl;    -   Het is a heteroaryl selected from the group consisting of    -   R₁ is selected from the group consisting of hydrogen, optionally        substituted alkyl, optionally substituted heteroaryl, C(O)R₁₀,        CH₂C(O)R₁₀, S(O)R₁₀, and SO₂R₁₀;    -   R₂ and R₃ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, alkynyl, aryl, cyano, aminoalkyl,        hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl,        alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino,        aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,        aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino,        aralkylcarbonylamino, alkylcarbonyl, aminosulfonyl,        alkylaminosulfonyl, and alkylsulfonyl;    -   R₅, R₆, R₇, and R₈ are independently selected from the group        consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl,        alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl,        nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol,        acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol;    -   R₁₀ is selected from the group consisting of amino, alkyl,        alkenyl, alkynyl, OR₁₁, alkylamino, dialkylamino, alkenylamino,        dialkylaminoalkenyl, cycloalkyl, aryl, heterocycle, heteroaryl,        aralkyl, arylalkenyl, arylalkynyl, and cycloalkylalkylamino;    -   R₁₁ is selected from the group consisting of hydrogen,        optionally substituted alkyl, and an alkalimetal.

Thus, the present invention is directed to provide a method fortreating, preventing or ameliorating neuronal loss following global andfocal ischemia; treating, preventing or ameliorating pain includingacute and chronic pain, and neuropathic pain; treating, preventing orameliorating convulsion and neurodegenerative conditions; treating,preventing or ameliorating manic depression; using as local anesthesics,antiarrhythmics, and treating tinnitus by administering a compound ofFormula I to a mammal in need of such treatment.

The present invention is also directed to novel compounds having FormulaI as described above; provided that:

-   1) when Het is (ii), and X is O, then R₁₀ is not alkyl, aralkyl,    aryl, or OR₁₁;-   2) when Het is (i) or (ii), then X is not NR₉;-   3) when Het is (iii), then X is not CH₂; and-   4) when Het is (iii), and X is O, then R₁₀ is not OR₁₁.

Optional substituents on optionally substituted groups, when nototherwise defined, include one or more groups independently selectedfrom the group consisting of halo, halo(C₁₋₆) alkyl, aryl, pyrimidine,cycloalkyl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl(C₁₋₆)alkyl,aryl(C₂₋₆)alkenyl, aryl(C₂₋₆)alkynyl, cycloalkyl(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, nitro, amino, ureido, cyano, C₁₋₆ acylamino, hydroxy,thiol, C₁₋₆ acyloxy, azido, C₁₋₆ alkoxy, carboxy, aminocarbonyl,carbamoyloxy, C₁₋₆ alkylsulfonylamino, C₁₋₆ acyl, and C₁₋₆ alkylthiolgroups mentioned above as long as the resulting compound is stable.Preferred optional substituents include: halo, halo(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, aminocarbonyl, carbamoyloxy, C₁₋₆ alkylsulfonylamino, C₁₋₆ acyland amino.

Preferably, R₁ is selected from the group consisting of an alkyloptionally substituted by halogen, hydroxy, carbamoyloxy, C₁₋₆ acyl,C₁₋₆ alkylsulfonylamino, aryl, preferably phenyl, or aminocarbonyl;C(O)R₁₀; CH₂C(O)R₁₀; or SO₂R₁₀, wherein R₁₀ is selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, OR₁₁, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkenylamino, heterocycle and mono- anddi-(C₁₋₆)alkylaminoalkenyl, and wherein R₁₁ is as defined above.

Preferably, R₁₀ is selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, OR₁₁, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkenylamino, mono- and di-(C₁₋₆)alkylamino(C₂₋₆)alkenyl, N-morpholinyl,N-pyrrolidinyl, and N-piperazinyl, all of which can be optionallysubstituted, wherein R₁₁ is as defined above.

Preferably, R₂ and R₃ are independently selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,amino(C₁-C₆)alkyl, amino, cyano, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, hydroxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, aminocarbonyl, C₁-C₆ alkylaminocarbonyl, C₆-C₁₀arylaminocarbonyl, C₆-C₁₀ aryl(C₁-C₆)alkylaminocarbonyl, C₁-C₆alkylcarbonylamino, C₆-C₁₀ arylcarbonylamino, and C₆-C₁₀aryl(C₁-C₆)alkylcarbonylamino, more preferably hydrogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, amino(C₁-C₆)alkyl, C₁-C₆ alkylthio and aminocarbonyl.

The groups R₅-R₈ each take place of a hydrogen atom that would otherwisebe present in any position on the aryl ring to which the R group isattached.

Preferably, R₅, R₆, R₇, and R₈ are independently selected from the groupconsisting of hydrogen, halo (preferably chloro or fluoro),halo(C₁-C₆)alkyl, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino,amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy,carbonylamido and C₁-C₆ alkylthiol.

One group of preferred compounds falling within the scope of Formula Iinclude compounds wherein R₁ is C(O)R₁₀ or SO₂R₁₀ where R₁₀ is definedabove, and is more preferably amino or C₁₋₆ alkyl. In this group ofcompounds, X is more preferably O or S, most preferably O.

Especially preferred in this group are compounds where R₅ and R₆ areeach hydrogen; R₂ and R₃ are both H; and R₇ and R₈ are selected from thegroup consisting of hydrogen, halo, halo(C₁-C₆)alkyl, C₁-C₆ alkyl,hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino, amide, hydroxy,thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy, carbonylamido and C₁-C₆alkylthiol.

Another group of preferred compounds includes compounds of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein

-   -   X is O or S, preferably O;    -   Het is a heteroaryl selected from the group consisting of        preferably (i) or (iii);    -   R₁ is C(O)R₁₀, CH₂C(O)R₁₀, or SO₂R₁₀ wherein R₁₀ is amino,        alkyl, N-morpholinyl, N-pyrrolidinyl or N-piperazinyl, more        preferably amino, all of which can be optionally substituted. R₁        is preferably C(O)R₁₀, where R₁₀ is amino, C₁-C₆ alkyl, or a        heterocycle, such as N-morpholinyl, N-pyrrolidinyl and        N-piperazinyl;    -   R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, C₁-C₆        alkylthio or C₁-C₆ alkylsulfinyl, with R₂ and R₃ preferably        being hydrogen; R₅ and R₆ are as defined above and are        preferably hydrogen; and R₇ and R₈ are independently selected        from the group consisting of hydrogen, halo, halo(C₁-C₆)alkyl,        C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,        carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆        acylamino, amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy,        carboxy, carbonylamido and C₁-C₆ alkylthiol;    -   provided that:

-   1) when Het is (ii), and X is O, then R₁₀ is not alkyl, aralkyl,    aryl or OR₁₁;

-   2) when Het is (iii), and X is O, then R₁₀ is not OR₁₁.

Exemplary preferred compounds that may be employed in this method ofinvention include, without limitation:

-   -   1-[4-(4-nitrophenoxy)phenyl]-1H-[1,2,4]triazole;    -   1-[4-(4-fluorophenoxy)phenyl]-3-methylpyrazole;    -   3-methyl-1-(4-phenoxyphenyl)pyrazole;    -   1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxamide;    -   1-(4-phenoxyphenyl)-1H-pyrazole-5-carboxamide;    -   1-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole-3-carboxamide;    -   1-[4-(4-nitrophenoxy)phenyl]-1H-[1,2,4]triazole-3-carboxamide;        and    -   1-[4-(4-chloro-2-fluorophenoxy)phenyl]-1H-pyrazole-3-carboxamide.

Another group of exemplary preferred compounds that may be employed inthis invention include 1-[4-(4-fluorophenoxy)phenyl]-5-methylpyrazole,1-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide, and4-(4-fluorophenoxy)phenylpyrazole.

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

Useful cycloalkyl groups are C₃₋₈ cycloalkyl. Typical cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

The term “heteroaryl” as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl,pyranyl, isobenzofuranyl, benzoxazonyl, chromenyl, xanthenyl,phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl,pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, thiazolyl,isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinylgroups).

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful alkyl groups include straight-chained and branched C₁₋₁₀ alkylgroups, more preferably C₁₋₆ alkyl groups. Typical C₁₋₁₀ alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,3-pentyl, hexyl and octyl groups. Also contemplated is a trimethylenegroup substituted on two adjoining positions on the benzene ring of thecompounds of the invention.

Useful alkenyl groups are C₂₋₆ alkenyl groups, preferably C₂₋₄ alkenyl.

Typical C₂₋₄ alkenyl groups include ethenyl, propenyl, isopropenyl,butenyl, and sec-butenyl.

Useful alkynyl groups are C₂₋₆ alkynyl groups, preferably C₂₋₄ alkynyl.

Typical C₂₋₄ alkynyl groups include ethynyl, propynyl, butynyl, and2-butynyl groups.

Useful arylalkyl groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by any of the above-mentioned C₆₋₁₄ aryl groups.Useful values include benzyl, phenethyl and naphthylmethyl.

Useful arylalkenyl groups include any of the above-mentioned C₂₋₄alkenyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups.

Useful arylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned C₆₋₁₄ arylgroups. Useful values include phenylethynyl and phenylpropynyl.

Useful heteroarylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful heteroarylalkenyl groups include any of the above-mentioned C₂₋₄alkenyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful heteroarylalkynyl groups include any of the above-mentioned C₂₋₄alkynyl groups substituted by any of the above-mentioned heteroarylgroups.

Useful cycloalkylalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned cycloalkylgroups.

Useful haloalkyl groups include C₁₋₁₀ alkyl groups substituted by one ormore fluorine, chlorine, bromine or iodine atoms, e.g. fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl andtrichloromethyl groups.

Useful hydroxyalkyl groups include C₁₋₁₀ alkyl groups substituted byhydroxy, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups.

Useful alkoxy groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful alkylthio groups include sulfur substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful acylamino groups are any C₁₋₆ acyl (alkanoyl) attached to anamino nitrogen, e.g. acetamido, propionamido, butanoylamido,pentanoylamido, hexanoylamido as well as aryl-substituted C₂₋₆substituted acyl groups.

Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g. acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy,hexanoyloxy and the like.

The term heterocycle is used herein to mean saturated or partiallyunsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ringsystem, which consists of carbon atoms and from one to four heteroatomsindependently selected from the group consisting of O, N, and S, whereinthe nitrogen and sulfur heteroatoms can be optionally oxidized, thenitrogen can be optionally quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring, and wherein the heterocyclic ring can be substituted oncarbon or on a nitrogen atom if the resulting compound is stable.Examples include, but are not limited to, pyrrolidine, piperazine,morpholine, imidazoline, pyrazolidine, benzodiazepines and the like.

Useful heterocycloalkyl groups include any of the above-mentioned C₁₋₁₀alkyl groups substituted by any of the above-mentioned heterocyclicgroups.

Useful alkylamino and dialkylamino groups are —NHR₂₀ and —NR₂₀R₂₁,wherein R₂₀ and R₂₁ are C₁₋₁₀ alkyl groups.

Aminocarbonyl group is —C(O)NH₂.

Useful alkylaminocarbonyl groups are carbonyl groups substituted by—NHR₂₀ and —NR₂₀R₂₁, wherein R₂₀ and R₂₁ are C₁₋₁₀ alkyl groups asdefined above.

Useful alkylthiol groups include any of the above-mentioned C₁₋₁₀ alkylgroups substituted by a —SH group.

Useful alkylsulfinyl groups include any of the above-mentioned C₁₋₁₀alkyl groups attached to a sulfinyl (—SO—).

Useful alkylsulfonyl groups include any of the above-mentioned C₁₋₁₀alkyl groups attached to a sulfonyl (—SO₂—).

A carbamoyloxy group is —O—C(O)—NH₂.

A carboxy group is —COOH.

An azido group is —N₃.

An ureido group is —NH—C(O)—NH₂.

An amino group is —NH₂.

An amide group is an organic radical having —NHC(O)— as a functionalgroup.

The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

The invention disclosed herein is also meant to encompass prodrugs ofthe disclosed compounds. Prodrugs are considered to be any covalentlybonded carriers which release the active parent drug in vivo. Examplesof prodrugs include esters or amides of Formula I with R₂-R₁₁ ashydroxyalkyl or aminoalkyl, and these may be prepared by reacting suchcompounds with anhydrides such as succinic anhydride.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfor example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein is also meant to encompass the disclosedcompounds being isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present invention is also meant toencompass racemic mixtures, resolved forms mixtures thereof, as well asthe individual enantiomers that may be separated according to methodsthat are well know to those of ordinary skill in the art. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule. The phrase“enantiomeric excess” refers to a mixture wherein one enantiomer ispresent is a greater concentration than its mirror image molecule.

Since the compounds of Formula I are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated employing these compounds. Therefore, the invention is relatedto a method of treating, preventing or ameliorating neuronal lossassociated with stroke, global and focal ischemia, CNS trauma,hypoglycemia and surgery, spinal cord trauma; as well as treating orameliorating neurodegenerative diseases including Alzheimer's disease,amyotrophic lateral sclerosis, Parkinson's disease, treating orameliorating anxiety, convulsions, glaucoma, migraine headache, andmuscle spasm. The compounds of Formula I are also useful as antitinnitusagents, antimanic depressants, as local anesthetics, and asantiarrhythmics; as well as for treating, preventing or amelioratingpain including surgical, chronic and neuropathic pain. In each instance,the methods of the present invention require administering to an animalin need of such treatment an effective amount of a sodium channelblocker of the present invention, or a pharmaceutically acceptable saltor prodrug thereof.

The invention is also directed to a method for treating disordersresponsive to the blockade of sodium channels in animals sufferingthereof.

Particular preferred embodiments of the aryl substituted heteroarylcompounds for use in method of this invention are represented bypreviously defined Formula I.

The compounds of this invention may be prepared using methods known tothose skilled in the art.

The synthesis of pyrazoles of Formula I can be prepared as shown inSchemes 1 and 2. The boronic acid coupling was accomplished using theprocedure of Lam, Y. S. et al. Tetrahedron Lett. 39. 2941-2944 (1998).

Triazoles of Formula I can be prepared as shown in Scheme 3, employingcommerically available 4-(1,2,4-triazol-1-yl)phenol (LancasterSynthesis).

The invention is also directed to ³H and ¹⁴C radiolabeled compounds ofFormula I and their use as radioligands for their binding site on thesodium channel. For example, one use of the labeled compounds of theinvention is the characterization of specific receptor binding. Anotheruse of the labeled compounds of the invention is an alternative toanimal testing for the evaluation of structure-activity relationships.The receptor assay is performed at a fixed concentration of a labeledcompound of Formula I and at increasing concentrations of a testcompound in a competition assay.

Tritiated compounds of Formula I can be prepared by introducing tritiuminto the compound of Formula I by, for example, catalytic dehalogenationwith tritium. This method includes reacting a suitablyhalogen-substituted precursor of a compound of Formula I with tritiumgas in the presence of a suitable catalyst, for example Pd/C, in thepresence or absence of a base. Other suitable methods for preparingtritiated compounds can be found in Filer, Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6.¹⁴C-labeled compounds can be prepared by employing starting materialshaving a 14C carbon.

The compounds of the present invention can be assessed byelectrophysiological assays in dissociated hippocampal neurons forsodium channel blocker activity. These compounds also can be assayed forbinding to the neuronal voltage-dependent sodium channel using ratforebrain membranes and [³H]BTX-B.

Sodium channels are large transmembrane proteins that are expressed invarious tissues. They are voltage sensitive channels and are responsiblefor the rapid increase of Na⁺ permeability in response to depolarizationassociated with the action potential in many excitable cells includingmuscle, nerve and cardiac cells.

One aspect of the present invention is the discovery of the mechanism ofaction of the compounds herein described as specific Na⁺ channelblockers. Based upon the discovery of this mechanism, these compoundsare contemplated to be useful in treating or preventing neuronal lossdue to focal or global ischemia, and in treating or preventingneurodegenerative disorders including ALS, anxiety, and epilepsy. Theyare also expected to be effective in treating, preventing orameliorating neuropathic pain, surgical pain, chronic pain and tinnitus.The compounds are also expected to be useful as antiarrhythmics,anesthetics and antimanic depressants.

The present invention is directed to compounds of Formula I that areblockers of voltage-sensitive sodium channels. According to the presentinvention, those compounds having preferred sodium channel blockingproperties exhibit an IC₅₀ of about 100 μM or less in theelectrophysiological assay described herein. Preferably, the compoundsof the present invention exhibit an IC₅₀ of 10 μM or less. Mostpreferably, the compounds of the present invention exhibit an IC₅₀ ofabout 1.0 μM or less. Substituted heteroaryl compounds of the presentinvention may be tested for their Na⁺ channel blocking activity by thefollowing electrophysiological and binding assays.

Electrophysiological Assay:

Cell Preparation:

HEK-293 (NaIIA-B2) cell line stably expressing the rBIIA isoform of Na⁺channels is established in-house. The cells are cultured using standardtechniques, as described previously (Verdoorn, T. A, et al., Neuron4:919-928 (1990)). For electrophysiology, cells are plated ontopoly-D-lysine pre-coated Cellware 35 mm Petri dishes (BIOCOAT, BectonDickinson) at a density of ˜10⁴ cells/dish on the day of re-seeding fromconfluent cultures. Our experience has been that cells are suitable forrecordings for 2-3 days after plating.

Patch-clamp Recordings of Voltage-sensitive Na⁺ Currents:

Whole-cell voltage-clamp recordings are made using conventionalpatch-clamp techniques (Hamill et al., Pfluegers Arch. 391:85-100(1981)) with an Axopatch 200A amplifier (Axon Instruments, Foster City,Calif.). The recording chamber is continuously superfused with theexternal solution (150 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10mM HEPES, 10 mM glucose, pH 7.4 adjusted with NaOH, osmolality ˜320mmol/kg) at a speed of about 1 mL/min. Recording pipettes were pulledfrom the thick-walled capillaries (WPI, Sarasota, Fla.) andfire-polished. The pipette resistances range from 1 to 3 MΩ when thepipettes are filled with internal solution containing (in mM): 130 CsF,20 NaCl, 2 MgCl₂, 10 EGTA, 10HEPES, pH adjusted to 7.4 with CsOH,osmolality ˜310 mmol/kg. Drugs and intervening wash-outs are appliedthrough a linear array of flow pipes (Drummond Microcaps, 2 μL, 64-mmlength). Compounds are dissolved in dimethylsulfoxide (DMSO) to make a30 mM stock solution, which is subsequently diluted into the externalsolution to give final concentrations of 0.1-100 μM. At the highest (1%)concentration, DMSO inhibits the size of Na⁺ current only slightly.Currents are recorded at room temperature (22-25° C.), filtered at 3 kHzwith an active 8-pole Bessel filter (Frequency Devices, Haverhill,Mass.), digitized at 10-50 μs intervals, and stored using Digidata 1200analog/digital interface with Pclamp6/Clampex software (AxonInstruments). Series resistance is cancelled typically by ˜75% whennecessary.

The following voltage pulse protocols A, B, C, and D are used to assessthe potency and kinetics of inhibition of the Na⁺ channels by thecompounds (FIGS. 1A-1D). Current-voltage relationship (IV-curve),protocol A, is used to report the voltage at which the maximal inwardNa⁺ current is achieved. This voltage is used throughout the experimentas testing voltage, V_(t). The steady-state inactivation (or,availability) curve, protocol C, is used to get the voltage at whichalmost complete (≧95%) inactivation of Na⁺ channels occurs; it serves asvoltage for conditioning prepulse, V_(c), throughout the experiment.Protocol B reports how fast the channels recover from inactivation athyperpolarized voltages. This permits us to set up the duration of thehyperpolarization gap which is used in measurement of the kinetics ofbinding of compounds to inactivated Na⁺ channels (protocol D). Channelrepriming under control conditions is fast (≧90% recovery during first5-10 ms). If a drug substantially retards the repriming process, then itbecomes possible (protocol D) to accurately measure the kinetics ofbinding of the inhibitor to inactivated channels as well as thesteady-state affinity (k₊ and K_(i)). To estimate k₊ values, thereduction in peak currents in successive trials with varying pre-pulseduration is plotted as a function of pre-pulse duration and the timeconstant (r) measured by mono-exponential fit. A plot of 1/τ as afunction of antagonist concentration then allows calculating of themacroscopic binding rates of the antagonists. To determine K_(i) valuesthe partial inhibition curves measured by fractional responses insteady-state are fitted with the logistic equation:I/I _(control)=1/(1+([antagonist]/K _(i))^(p)),  Eq. 2where I_(control) is the maximal Na⁺ current in the absence ofantagonist, is the drug concentration, K_(i) is the concentration ofantagonist that produces half maximal inhibition, and p is the slopefactor.In vitro Binding Assay:

The ability of compounds of the present invention to modulate eithersite 1 or site 2 of the Na⁺ channel is determined following theprocedures fully described in Yasushi, J. Biol. Chem. 261:6149-6152(1986) and Creveling, Mol. Pharmacol. 23:350-358 (1983), respectively.Rat forebrain membranes are used as sources of Na⁺ channel proteins. Thebinding assays are conducted in 130 μM choline chloride at 37° C. for60-minute incubation with [3 ] saxitoxin and [³H] batrachotoxin asradioligands for site 1 and site 2, respectively.

In vivo Pharmacology:

The compounds of the present invention may be tested for in vivoanticonvulsant activity after i.v., p.o. or i.p. injection using anumber of anticonvulsant tests in mice, including the maximumelectroshock seizure test (MES). Maximum electroshock seizures areinduced in male NSA mice weighing between 15-20 g and maleSprague-Dawley rats weighing between 200-225 g by application of current(50 mA, 60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C., mice;99 mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C., rats)using a Ugo Basile ECT device (Model 7801). Mice are restrained bygripping the loose skin on their dorsal surface and saline-coatedcorneal electrodes are held lightly against the two corneae. Rats areallowed free movement on the bench top and ear-clip electrodes are used.Current is applied and animals are observed for a period of up to 30seconds for the occurrence of a tonic hindlimb extensor response. Atonic seizure is defined as a hindlimb extension in excess of 90 degreesfrom the plane of the body. Results are treated in a quantal manner.

The compounds may be tested for their antinociceptive activity in theformalin model as described in Hunskaar, S., O. B. Fasmer, and K. Hole,J. Neurosci. Methods 14. 69-76 (1985). Male Swiss Webster NIH mice(20-30 g; Harlan, San Diego, Calif.) are used in all experiments. Foodis withdrawn on the day of experiment. Mice are placed in Plexiglassjars for at least 1 hour to accommodate to the environment. Followingthe accommodation period mice are weighed and given either the compoundof interest administered i.p. or p.o., or the appropriate volume ofvehicle (10% Tween-80). Fifteen minutes after the i.p. dosing, and 30minutes after the p.o. dosing mice are injected with formalin (20 μL of5% formaldehyde solution in saline) into the dorsal surface of the righthind paw. Mice are transferred to the Plexiglass jars and monitored forthe amount of time spent licking or biting the injected paw. Periods oflicking and biting are recorded in 5 minute intervals for 1 hour afterthe formalin injection. All experiments are done in a blinded mannerduring the light cycle. The early phase of the formalin response ismeasured as licking/biting between 0-5 mm, and the late phase ismeasured from 15-50 min. Differences between vehicle and drug treatedgroups are analyzed by one-way analysis of variance (ANOVA). A P value≦0.05 is considered significant. Having activity in blocking the acuteand second phase of formalin-induced paw-licking activity, the compoundsare considered to be efficacious for acute and chronic pain.

The compounds may be tested for their potential for the treatment ofchronic pain (antiallodynic and antihyperalgesic activities) in theChung model of peripheral neuropathy. Male Sprague-Dawley rats weighingbetween 200-225 g are anesthetized with halothane (1-3% in a mixture of70% air and 30% oxygen) and their body temperature is controlled duringanesthesia through use of a homeothermic blanket. A 2-cm dorsal midlineincision is then made at the L5 and L6 level and the para-vertibralmuscle groups are retracted bilaterally. L5 and L6 spinal nerves arethen exposed, isolated, and tightly ligated with 6-0 silk suture. A shamoperation is performed exposing the contralateral L5 and L6 spinalnerves as a negative control.

Tactile Allodynia:

Rats are transferred to an elevated testing cage with a wire mesh floorand allowed to acclimate for five to ten minutes. A series ofSemmes-Weinstein monofilaments are applied to the plantar surface of thehindpaw to determine the animal's withdrawal threshold. The firstfilament used possesses a buckling weight of 9.1 gms (.96 log value) andis applied up to five times to see if it elicits a withdrawal response.If the animal has a withdrawal response then the next lightest filamentin the series would be applied up to five times to determine if it couldelicit a response. This procedure is repeated with subsequent lesserfilaments until there is no response and the lightest filament thatelicited a response is recorded. If the animal does not have awithdrawal response from the initial 9.1 gms filament then subsequentfilaments of increased weight are applied until a filament elicits aresponse and this filament is then recorded. For each animal, threemeasurements are made at every time point to produce an averagewithdrawal threshold determination. Tests are performed prior to and at1, 2, 4 and 24 hours post-drug administration. Tactile allodynia andmechanical hyperalgesia tests are conducted concurrently.

Mechanical Hyperalgesia:

Rats are transferred to an elevated testing cage with a wire mesh floorand allowed to acclimate for five to ten minutes.

A slightly blunted needle is touched to the plantar surface of thehindpaw causing a dimpling of the skin without penetrating the skin.Administration of the needle to control paws typically produces a quickflinching reaction, too short to be timed with a stopwatch andarbitrarily given a withdrawal time of 0.5 sec. The operated side paw ofneuropathic animals exhibits an exaggerated withdrawal response to theblunted needle. A maximum withdrawal time of ten seconds is used as acutoff time. Withdrawal times for both paws of the animals are measuredthree times at each time point with a five-minute recovery periodbetween applications. The three measures are used to generate an averagewithdrawal time for each time point. Tactile allodynia and mechanicalhyperalgesia tests are conducted concurrently.

The compounds may be tested for their neuroprotective activity afterfocal and global ischemia produced in rats or gerbils according to theprocedures described in Buchan et al. (Stroke, Suppl. 148-152 (1993))and Sheardown et al. (Eur. J. Pharmacol. 236:347-353 (1993)) and Grahamet al. (J. Pharmacol. Exp. Therap. 276:1-4 (1996)).

The compounds may be tested for their neuroprotective activity aftertraumatic spinal cord injury according to the procedures described inWrathall et. al. (Exp. Neurology 137:119-126 (1996)) and Iwasaki et. al.(J. Neuro Sci. 134:21-25 (1995)).

Compositions within the scope of this invention include all compositionswherein the compounds of the present invention are contained in anamount that is effective to achieve its intended purpose. Whileindividual needs vary, determination of optimal ranges of effectiveamounts of each component is within the skill of the art. Typically, thecompounds may be administered to mammals, e.g. humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the mammal beingtreated for epilepsy, neurodegenerative diseases, anesthetic,arrhythmia, manic depression, and pain. For intramuscular injection, thedose is generally about one-half of the oral dose.

In the method of treatment or prevention of neuronal loss in global andfocal ischemia, brain and spinal cord trauma, hypoxia, hypoglycemia,status epilepsy and surgery, the compound can be administrated byintravenous injection at a dose of about 0.025 to about 10 mg/kg.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound. The unit dose maybe administered one or more times daily as one or more tablets eachcontaining from about 0.1 to about 10, conveniently about 0.25 to 50 mgof the compound or its solvates.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the particular heteroaryl compound of the present invention with asolution of a pharmaceutically acceptable non-toxic acid such ashydrochloric acid, fumaric acid, maleic acid, succinic acid, aceticacid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalicacid, dichloroacetic acid, and the like. Basic salts are formed bymixing a solution of the heteroaryl compound of the present inventionwith a solution of a pharmaceutically acceptable non-toxic base such assodium hydroxide, potassium hydroxide, choline hydroxide, sodiumcarbonate and the like.

The pharmaceutical compositions of the invention may be administered toany animal that may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humans,although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, or buccal routes.Alternatively, or concurrently, administration may be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetyl-cellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations, which can be used rectally,include, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances which increase the viscosity of the suspension, andinclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

EXAMPLE 1 1-[4-(4-Fluorophenoxy)phenyl]-3-methylpyrazole

a) 4-(4-Fluorophenoxy)phenylhydrazine Hydrochloride:

A suspension of finely powdered 4-fluoro-4′-aminodiphenyl ether (2.00 g,9.84 mmol) in 10 mL of water was cooled in an ice-water bath and 19.4 mLof conc. HCl was added dropwise via addition funnel. The resultingmixture was cooled to −5° C. in an acetone-ice bath and a solution ofsodium nitrite (crystalline; 0.714 g, 10.3 mmol) in 8 mL of cold waterwas added dropwise to the reaction at such a rate that the temperatureremained between and −5 and 0° C. A solution of SnCl₂-2H₂O (6.66 g, 29.5mmol) in 20 mL of conc. HCl at −20° C. was treated with the reactionmixture added in portions, maintaining the temperature below −10° C. Agrey ppt. formed immediately and the resulting mixture was stirred at−20° C. for 90 min. The solid was isolated by filtration and washed withcold EtOH (2×10 mL). The crude hydrazine, 2.36 g, was carried on withoutpurification.

b) 1-[4-(4-Fluorophenoxy)phenyl]-3-methylpyrazole:

A suspension of the hydrazine (500 mg, 2.05 mmol) in 5.5 mL of 1:1EtOH/water was treated with 300 μL (299 mg, 2.03 mmol) of 90%acetylacetaldehyde dimethylacetal and the resulting mixture was warmedwith a heat gun for 2 min. The reaction was allowed to cool andextracted with hexane (4×10 mL). The pooled organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The residue was subjectedto column chromatography (silica gel, 10% EtOAc/heaxne) affording 134 mg(24%) of the title compound as a white solid, mp 80-81° C. ¹H NMR(CDCl₃): δ 7.74 (s, 1H), 7.58 (d, 2H, J 8.4 Hz), 7.06-6.95 (m, 6H), 6.23(s, 1H), 2.37 (s, 3H).

EXAMPLE 2 1-(4-Phenoxyphenyl)-1H-pyrazole-3-carboxamide and1-(4-phenoxyphenyl)-1H-pyrazole-5-carboxamide

a) 3-Ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole and5-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole:

To a suspension of 4-phenoxyphenylboronic acid (1.70 g, 7.85 mmol),ethyl 3-pyrazolecarboxylate (0.55 g, 3.92 mmol), copper(II)acetate (1.1g, 5.89 mmol) and 4 Å molecular sieves (powdered and heated at 200° C.for 2 h prior to use) in 30 mL of anhydrous THF was added 0.6 mL ofpyridine. The reaction was stirred open to air at room temperature for 2days and then filtered and the filtrate was concentrated to dryness. Thecrude product was purified by flash chromatography, eluting with 15%EtOAc/hexane, affording 5-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole(Rf=0.6, 55 mg, 4.6%) and3-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (Rf=0.5, 125 mg,10.3%).

b) 1-(4-Phenoxyphenyl)-1H-pyrazole-3-carboxamide:

A solution of 3-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (120 mg,0.39 mmol) in 5 mL of a 2N solution of ammonia in MeOH was stirred at rtfor 4 d. TLC showed incomplete reaction and the solution was transferredto a sealed tube and heated at 70° C. overnight. The reaction wasconcentrated and purified by preparative TLC, eluting with 50%EtOAc/hexane, to yield 1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxamide(Rf=0.26, 56 mg, 52%), mp 165-167° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.50(d, J=2.7 Hz, 1H, pyrazole), 7.92 (d, J=9.0 Hz, 2H, Phenyl), 7.71 (br,1H, NH₂), 7.43 (m, 2H, Phenoxy), 7.39 (br, 1H, NH₂), 7.18 (m, 1H,Phenoxy), 7.17 (d, J 9.0 Hz, 2H, Phenyl), 7.07 (m, 2H, Phenoxy), 6.87(d, J=2.7 Hz, 1H, pyrazole).

Starting with 5-ethoxycarbonyl-1-(4-phenoxyphenyl)-1H-pyrazole (50 mg,0.16 mmol), the method described above gave1-(4-phenoxyphenyl)-1H-pyrazole-5-carboxamide (25 mg, 55%), mp 142-144°C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (br s, 1H, NH₂), 7.70 (d, J=1.8 Hz,1H, pyrazole), 7.54 (br , 1H, NH₂), 7.42 (m, 2H, Phenoxy), 7.39 (d,J=9.0 Hz, 2H, Phenyl), 7.20 (m, 1H, Phenoxy), 7.08 (m, 2H, Phenoxy),7.06 (d, J=9.0 Hz, 2H, Phenyl), 6.90 (d, J=1.8 Hz, 1H, pyrazole).

EXAMPLE 3 1-[4-(4-Nitrophenoxy)phenyl]-1H-[1,2,4]triazole

A mixture of 1-fluoro-4-nitrobenzene (0.17 mL, 1.6 mmol),4-{[1,2,4]triazol-1-yl}phenol (0.26 g, 1.58 mmol), and potassiumcarbonate (1.69 g, 12.2 mmol) in DMF was refluxed overnight. Thereaction was cooled to room temperature, then partitioned between waterand ethyl acetate. The aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with an aqueous sodium hydroxidesolution (2N), water (2 times), dried over sodium sulfate, filtered, andevaporated under reduced pressure to give a yellow solid. Purificationby column chromatography (silica gel; 1:1 hexane/ethyl acetate) andrecrystallization from chloroform/hexane afforded 165 mg (37%) of thetitle compound as a yellow solid, mp 131-132° C. ¹H-NMR (CDCl₃): δ 8.55(s, 1H), 8.25 (d, J=9 Hz, 2H), 8.12 (s, 1H), 7.75 (d, J=9 Hz, 2H), 7.24(d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H).

EXAMPLE 4 Anticonvulsant Activity of Compounds of the Invention

The ability of compounds of the present invention to block maximalelectroshock-induced seizures (MES) is determined as described earlier.

A compound of the present invention is administered p.o. to mice 30minutes before the test procedure. The compound exhibits protectionagainst MES with an ED₅₀ (the dose provided protection of 50% ofanimals) of preferably below 10 mg/kg.

Activity of 1-(4-phenoxyphenyl)-1H-pyrazole-3-carboxamide asanticonvulsant, MES i.v. ED₅₀ in mouse 0.7 mg/kg.1-[4-(4-Nitrophenoxy)phenyl]-1H-[1,2,4]triazole, MES po ED₅₀ 6.6 mg/kg.1-(4-phenoxyphenyl)-1H-pyrazole-5-carboxamide, MES i.v. ED₅₀ 10.0 mg/kg.

EXAMPLE 5 Activity of Compound of the Invention as Sodium ChannelBlocker

Compounds of the invention are tested in the electrophysiological andbinding assays described above and produce dose-dependent inhibition ofvoltage-gated sodium currents recorded in HEK-293 cells stablyexpressing the rBIIA isoform of Na⁺ channels. The blocking effect ofpreferrred compounds on Na⁺ currents is highly sensitive to the holdingvoltage, indicating that the compounds bind to voltage-sensitive Na⁺channels in their inactivated states and have weak potency towards Na⁺channels in their resting states (Ragsdale et al., Mol. Pharmacol.40:756-765 (1991); Kuo and Bean, Mol. Pharmacol. 46:716-725 (1994)). Theapparent antagonist dissociation constant (K_(d)) of preferred compoundsfor inactivated sodium channels is less than 400 nM.1-(4-Phenoxyphenyl)-1H-pyrazole-3-carboxamide was tested in rBIIAisoform of sodium channel and had Ki 0.35 μM.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

1. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X is one of O, S or CH₂; Het is

R₁ is selected from the group consisting of hydrogen, optionally substituted alkyl, heteroaryl optionally substituted with one or more groups independently selected from the group consisting of halo, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, hydroxy, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy, aminocarbonyl, carbamoyloxy, C₁₋₆ alkylsulfonylamino, C₁₋₆ acyl and amino, C(O)R₁₀, CH₂C(O)R₁₀, S(O)R₁₀, and SO₂R₁₀; R₂ and R₃ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cyano, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, aminosulfonyl, alkylaminosulfonyl, and alkylsulfonyl; R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkylthiol; R₁₀ is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR₁₁, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, aralkyl, arylalkenyl, arylalkynyl, and cycloalkylalkylamino, all of which are optionally substituted; and R₁₁ is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal.
 2. A compound of claim 1, wherein R₁ is selected from the group consisting of an alkyl optionally substituted by halogen, hydroxy, carbamoyloxy, C₁₋₆ acyl, C₁₋₆ alkylsulfonylamino, aryl, or aminocarbonyl; C(O)R₁₀; CH₂C(O)R₁₀; or SO₂R₁₀, wherein R₁₀ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, OR₁₁, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆ alkenylamino, heterocycle and mono- and di-(C₁₋₆)alkylaminoalkenyl, and R₁₁ is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal.
 3. A compound of claim 2, wherein R₁₀ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, OR₁₀, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆ alkenylamino, and di(C₁₋₆)alkylamino(C₂₋₆)alkenyl.
 4. A compound of claim 3, wherein R₂ and R₃ are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, amino(C₁-C₆)alkyl, amino, C₁-C₆ alkylthio, cyano, C₁-C₆ alkylsulfinyl, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkoxy, aminocarbonyl, C₁-C₆ alkylaminocarbonyl, C₆-C₁₀ arylaminocarbonyl, C₆-C₁₀ aryl(C₁-C₆)alkylaminocarbonyl, C₁-C₆ alkylcarbonylamino, C₆-C₁₀ arylcarbonylamino, and C₆-C₁₀ aryl(C₁-C₆)alkylcarbonylamino.
 5. A compound of claim 3, wherein R₂ and R₃ are independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino(C₁-C₆)alkyl, C₁-C₆ alkylthio and aminocarbonyl.
 6. A compound of claim 1, wherein R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, halo, halo(C₁-C₆)alkyl, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino, amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy, carbonylamido and C₁-C₆ alkylthiol.
 7. A compound of claim 1, wherein R₁ or R₂ is C(O)R₁₀ or SO₂R₁₀.
 8. A compound of claim 7, wherein where R₁₀ is amino or C₁₋₆ alkyl.
 9. A compound of claim 8, wherein X is O or S.
 10. A compound of claim 9, wherein: R₅ and R₆ are each hydrogen; R₃ and R₂ are both H; and R₇ and R₈ are selected from the group consisting of hydrogen, halo, halo(C₁-C₆)alkyl, C₁-C₆ alkyl, hydxoxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino, amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy, carbonylamido and C₁-C₆ alkylthiol.
 11. A compound of claim 1, wherein: R₁ is C(O)R₁₀, CH₂C(O)R₁₀, or SO₂R₁₀; X is O or S; R₁₀ is amino, optionally substituted C₁-C₆ alkyl, or a heterocycle; R₂, and R₃ are independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylthio or C₁-C₆ alkylsulfinyl, R₅ and R₆ are as defined in claim 1, and R₇ and R₈ are independently selected from the group consisting of hydrogen, halo, halo(C₁-C₆)alkyl, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino, amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy, carbonylamido and C₁-C₆ alkyithiol.
 12. A compound of claim 11, wherein R₅ and R₆ are both hydrogen.
 13. A compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X is O or S; Het is

R₁ is C(O)R₁₀, CH₂C(O)R₁₀, or SO₂R₁₀ wherein R₁₀ is amino, all of which are optionally substituted; R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylthio or C₁-C₆ alkylsulfinyl; and R₅, R₆, R₇ and R₈ are independently selected from the group consisting of hydrogen, halo, halo(C₁-C₆)alkyl, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino, amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy, carbonylamido and C₁-C₆ alkylthiol.
 14. A compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X is O or S; Het is

R₁ is C(O)R₁₀, wherein R₁₀ is amino, all of which are optionally substituted; R₂ and R₃ are independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylthio or C₁-C₆ alkylsulfinyl; and R₅, R₆, R₇ and R₈ are independently selected from the group consisting of hydrogen, halo, halo(C₁-C₆)alkyl, C₁-C₆ alkyl, hydroxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl, nitro, amino, C₁-C₆ acylamino, amide, hydroxy, thiol, C₁-C₆ acyloxy, C₁-C₆ alkoxy, carboxy, carbonylamido and C₁-C₆ alkylthiol.
 15. A compound of claim 14, wherein X is O.
 16. A compound having the Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X is NR₉C(O) or C(O)NR₉, where R₉ is hydrogen or C₁-C₁₀ alkyl; Het is

R₁ is SO₂R₁₀; R₂ and R₃ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cyano, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxyalkyl, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aralkylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, alkylcarbonyl, aminosulfonyl, alkylaminosulfonyl, and alkylsulfonyl; R₅, R₆, R₇, and R₈ are independently selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino, ureido, cyano, acylamino, amide, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido and alkyithiol; R₁₀ is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, OR₁₁, alkylamino, dialkylamino, alkenylamino, dialkylaminoalkenyl, cycloalkyl, heterocycle, heteroaryl, aryl, aralkyl, arylalkenyl, arylalkynyl, and cycloalkylalkylamino, all of which are optionally substituted; and R₁₁ is selected from the group consisting of hydrogen, optionally substituted alkyl, and an alkalimetal.
 17. A pharmaceutical composition, comprising the compound of any one of claims 1, 13, 14, or 16 and a pharmaceutically acceptable carrier.
 18. A method of treating a disorder responsive to the blockade of sodium channels in a mammal suffering therefrom, comprising administering to a mammal in need of such treatment effective amount of the compound as claimed in any one of claims 1, 13, 14, or
 16. 19. A method for treating or ameliorating neuronal loss following global and focal ischemia; treating or ameliorating neurodegenerative conditions; treating or ameliorating pain or tinnitus; treating or ameliorating manic depression; providing local anesthesia; treating arrhythmias, or treating convulsions, comprising administering to a mammal in need of such treatment an effective amount of the compound as claimed in any one of claims 1, 13, 14, or
 16. 20. The method of claim 19, wherein the method is for treating or ameliorating pain and said pain is one of neuropathic pain, surgical pain or chronic pain.
 21. A method of alleviating seizure activity in an animal subject, comprising administering to a mammal in need of such treatment an effective amount of a compound of anyone of claims 1, 13, 14, or
 16. 